1. Field of the Invention
The present invention relates to .beta.-Amino-.alpha.-hydroxycarboxylic acid derivatives and salts thereof which are useful as human immunodeficiency virus (HIV) protease inhibitors and/or as intermediates for synthesizing the inhibitors.
2. Description of the Related Art
Heretofore, various efforts for the therapy of acquired immunodeficiency syndrome (AIDS) and the prevention of infection of the human immunodeficiency virus (HIV) by inhibiting the HIV protease have been performed. Some peptide derivatives have been proposed as the inhibitor, for example, Japanese Unexamined Patent Publication Nos. 117615, 209854, 202898, 202899, 204475 (1990) and Review: J. Med. Chem., 34, 2305 (1991). Some HIV protease inhibitors involve the use of hydroxy amino acid isosteres, and in addition, a formation of hydrogen bond between the hydroxy group and Asp25 in the active site of HIV protease was proposed.
Also, a renin inhibitor having a .beta.-amino-.alpha.-hydroxycarboxylic residue shown by the following general formula (6) as an amino acid isostere in a peptide chain was proposed, for example, in Japanese Unexamined Patent Publication No. 101098 (1990) and the preparation of said carboxylic acid was reported in relation to an anti-cancer agent, for example, in J. Med. Chem., 20, 510, (1977), ibid., 33, 2707 (1990).
Formula (6) has the following structure: ##STR2##
In the general formula (6), R.sup.8 represents a straight or branched lower alkyl group, a cycloalkyl-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, an amino-lower alkyl group, or an aryl-lower alkyl group.
However, no .beta.-amino-.alpha.-hydroxy-carbocyclic acid mentioned above has been used as amino acid isostere in an HIV protease inhibitor.
Further, compounds having the following basic structure represented by general formula (3) and (3') are not known. ##STR3##
wherein n represents 1 or 2, A represents a hydrogen atom or a peptide N-terminal protective group, B.sup.1, B.sup.2, B.sup.3, B.sup.5, and B.sup.6 represents independently a single bond or an amino acid residue, optionally the amino group of said amino acid can be substituted with a hydrocarbon residue having 12 or less carbon atoms, B.sup.7 represents a single bond or an amino acid residue represented by following formula (4) with a proviso that XR.sup.2 R.sup.3 represents the following general formula (4') when B.sup.7 is a single bond, X represents a nitrogen atom or an oxygen atom, R.sup.1 represents a lower alkyl group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group optionally substituted with an amino group, a mercapto group, a hydroxy group, a carboxy group, a carbamoyl group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group or a heterocyclic group, R.sup.2 and R.sup.3 each represents a hydrogen atom or an optionally substituted hydrocarbon group having 12 or less carbon atoms which form cycles by forming bonds between said carbon atoms which may optionally be replaced with an oxygen, nitrogen or sulfur atom with the proviso that no R.sup.3 is present when X represents oxygen atom, R.sup.4 represents a carbamoyl group, a carboxy group, a cyano group, an alkoxycarbonyl group, a hydroxy group, a lower alkoxy group, a lower alkylthio group, a lower alkanesulfonyl group, a sulfonyl group, a lower alkanesulfinyl group or a sulfamoyl group, R.sup.5 represents an optionally substituted arylmethyl group, and R.sup.6 has the same meaning as that in the following general formula (4): ##STR4##
wherein R.sup.6 and R.sup.7 represent a bivalent hydrocarbon group forming a 5-7 membered ring optionally substituted or fused with the other 5-7 membered ring, and a part of carbon atoms in said rings optionally replaced with hetero atoms.